East German Pat. No. 67,130 to Becker et al describes a procedure for the synthesis of 3,5-disubstituted-1,2,4-triazoles useful as intermediates. The product triazoles are formed as follows. A starting material of structure I ##STR2## wherein R.sub.1 is alkyl, aryl, aralkyl, alkoxyalkyl, acylaminoalkyl, or a heterocyclic group and R.sub.2 is hydrogen, alkyl, or aryl, is treated with acylating agent such as an acid chloride or acid anhydride or an alkylating gent such as an alkylhalide. Depending on conditions, the product is isolated directly (or as its salt) or an intermediate product or residue of undefined structure or composition is first isolated and then converted to the triazole product by thermolysis or hydrolysis. A by-product is described in several examples which is a diacyl (or dialkyl) hydrazine presumably arising from the 1,2-hydrazino protion of the starting thiazole that is lost in the course of the reaction.
In Example 10 of the Becker et al patent, N-4-(3,5-dimethyl-1,2,4-triazolyl)benzamidine is reacted with acetic anhydride at 170.degree. C. for 2-3 hours with evaporation of the volatile materials to form a residue ("Ruckstand") of unknown composition and utility. The residue is heated for 3 hours in water to give the 3-methyl-5-phenyl-1,2,4-triazole product.
Becker et al neither identify the components of the residue nor separate out or isolate such components. However, it is believed that about one-half of the Ruckstand or residue is a mixture of various by-products, and the remainder is a mixture of 1-acetyl-5-methyl-3-phenyl-1H-1,2,4-triazole and 1-acetyl-3-methyl-5-phenyl-1H-1,2,4-triazole in about a 90:10 ratio to each other.
Becker et al in a paper entitled "A Novel Synthesis for 3-Substituted 1,2,4-Triazoles," Journal fur praktische Chemie. Volume 311, 1969, pages 477-489, disclose the preparation of 3-substituted-1,2,4-triazoles including 3-phenyl-1,2,4-triazoles of the structure ##STR3## wherein R.sup.1 can be ethoxy, methyl, ethyl or n-propyl. A general preparation for 1-acetyl-3-phenyl-1,2,4-triazole and 1-propionyl-3-phenyl-1,2,4-triazole is set out on page 487.
U.S. Pat. No. 4,006,159 to Newman discloses mixtures of acyl-substituted 1,2,4-triazole-3-carboxamides which may be presented by the following structural formulae:
______________________________________ ##STR4## 1-acyl-s-triazole-3- carboxamide ##STR5## 2-acyl-s-triazole-3- carboxamide ##STR6## 4-acyl-s-triazole-3- carboxamide ______________________________________
wherein each mixture consists of all three forms wherein R is the same in each form and wherein R is hydrogen, alkyl having up to 15 carbon atoms; cycloalkyl having from 3 to 8 carbon atoms; phenyl; ortho-, meta-, or para-hydroxyphenyl; ortho-, meta-, or paramethoxyphenyl; or adamantyl. The above mixture is said to be useful as anti-viral agents.
The present invention relates to 1-acyl-3(5)-alkyl-5(3)-phenyl-1,2,4-triazoles which are useful as antiinflammatory agents and have the structure ##STR7## wherein R is lower alkyl or cycloalkyl, R.sup.1 is lower alkyl or cycloalkyl, and X is hydrogen, halogen, lower alkyl, lower alkoxy, nitro or trifluoromethyl.
The preferred compounds of the invention are those of formula I wherein X is in the para position and is halogen, R is methyl or ethyl, and R.sup.1 is methyl or ethyl.
The term "lower alkyl" as used herein refers to alkyl groups having 1 to 7 carbons, preferably 1 to 4 carbons, including straight or branched chain groups, such as methyl, ethyl, n-propyl, i-propyl, 2-propylbutyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, and n-heptyl and the various branched chain isomers thereof.
The term "lower alkoxy" as used herein refers to lower alkyl groups as defined above attached to an oxygen atom, with methoxy being preferred.
The term "cycloalkyl" as used herein refers to saturated carbocyclic radicals containing 3 to 7 carbons in the ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
The term "halogen" as employed herein refers to chlorine, bromine, iodine or fluorine with chlorine and bromine being preferred.
The compounds of formulae I and II may be prepared according to a modification of the procedure outlined in East German Pat. No. 67,130 (1969), Chem. Abst. 71, 124441e. Thus, a benzonitrile of the structure ##STR8## is condensed with an amino-1,2,4-triazole of the structure ##STR9## in the presence of an alkali metal hydride, such as sodium hydride or lithium hydride, and a non-reacting solvent such as dimethylformamide, dimethyl sulfoxide or dioxane, to form a compound of the structure ##STR10##
The formula V compound is then reacted with an acid anhydride ##STR11## such as acetic anhydride, propionic anhydride, butyric anhydride and the like to yield a mixture of the formulae I and II compounds of the invention.
The mixture may be separated into the formula I compund and the formula II compound by crystallization from an appropriate solvent, such as ethanol or isopropyl ether or by chromatography on a suitable adsorbent, such as silica gel. The formulae I and II compounds may be separately recovered in crystalline form each at least 95% and preferably 99% pure.
The starting triazole of structure IV is prepared by techniques well known in the art (e.g., see Th. Curtius and G. M. Dedichen, J. Prakt. Chem., 50, 241 (1894), Beil. 26, 29). Thus, the formula IV compound may be prepared by reaction of hydrazine and an alkyl cyanide VII RCN wherein R is lower alkyl or cycloalkyl, under high temperatures ranging from 100 to 250, preferably from 140.degree. to 190.degree. C., for periods of 0.5 to 48 hours in a sealed system, if necessary.
The compounds of formula I have antiinflammatory activity as measured by the mouse active arthus (MAA) test and/or other related tests and are useful as antiinflammatory agents and may be used, for example, in a manner similar to phenylbutazone or indamethacin. They may be used to decrease joint swelling, tenderness, pain and stiffness in mammalian species, e.g., in conditions such as rheumatoid arthritis. The quantity administered ranges from about 1 mg to about 150 mg per kg and preferably from about 5 mg to about 75 mg per kg of body weight per day.
A compound of formula I or II can be administered orally or parenterally (for example, intraperitoneally, subcutaneously, intramuscularly or intravenously). Powders can be prepared by comminuting the active ingredient with a similarly comminuted diluent such as starch or lactose. Suitable forms for oral administration include capsules, tablets, troches, elixirs, wafer, chewing gum, syrups, and a suitable form for parenteral administration in a sterile injectable. Such unit dosage forms are prepared by compounding with a conventional vehicle, excipients, binders, preservatives, stabilizers, flavoring agents or the like as called for by acceptable pharmaceutical practice. Also, the compounds used in this invention can be formulated with other pharmaceutically active compounds.
The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate, a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen or cherry flavoring. When the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit, for instance, tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compounds, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.